Regulation of eye development by an Opsin 5-dopamine pathway. Neuropsin (OPN5) is an atypical opsin that we show is expressed in retinal ganglion cells of the vertebrate retina (we call these ip5RGCs). OPN5 is known to respond to near-UV wavelengths and to photoentrain a retinal circadian clock. Beyond this, very little is known about the physiological function of neuropsin in any tissue. In this application we reveal that during development of the eye, an OPN5 response pathway regulates levels of the crucial neuromodulator dopamine (DA). DA is known to have several functions in the visual system but among them, the best characterized is its role in regulating the adaptive response to nighttime and daytime lighting. We also reveal that DA has an important role directly influencing vascular development within the eye. Preliminary data suggest that DA acts as a negative regulator of vascular responses to promote hyaloid vessel regression and suppress retinal angiogenesis. Thus, DA acts as a counter to VEGFA, a pro-vascular stimulus. Our preliminary findings suggest the central hypothesis: An OPN5-dopamine pathway regulates vascular development of the eye. Our hypothesis incorporates the dual suggestions that OPN5 regulates DA activity and that DA directly regulates vascular development in the eye. We propose three experimental Aims designed to address the relationship between neuropsin activity and DA production:
Aim 1 : To determine whether ip5RGCs form physical connections with dopaminergic amacrine cells.
Aim 2 : To assess whether OPN5 regulates dopamine acutely or via the retinal circadian clock.
Aim 3 : To determine the mechanism by which DA regulates vascular development in the eye. When complete, these analyses will provide important new insights on the role of neuropsin in the physiology of the visual system. This analysis is also clinically relevant because a DA-vascular pathway is probably the explanation for the association between DA treatment of premature infants (for hypotension) and the potentially blinding vascular overgrowth of severe retinopathy of prematurity.
Weproposetostudyanewlydiscoveredsensorycellintheretinathatexpressesthelight-?detection proteinOPN5.WehaveshowthatOPN5intheretinaisimportantforregulationoftheneuromodulator dopamine,andthatOPN5regulatesvasculardevelopmentintheeyeviaadopaminepathway.Thishas implicationsfortheuseofdopamineinprematureinfantstotreathypotension,apracticethatresultsina higherriskofvasculardiseaseintheretina(retinopathyofprematurity).
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